The gameplay in Command & Conquer 4 no longer follows the same resource-gathering dynamic as previous games in the series. In the main game mode, the player must capture control nodes scattered across a map, and retain more nodes than the enemy player, gaining enough points over time to win the match. Command & Conquer 4 utilizes class-based gameplay as well as some RPG elements.

There are two playable factions: the GDI and the Brotherhood of Nod. Each faction is split into three upgradeable classes: offence, defense and support, each with their own specialized focus. The classes consist mostly of their own unique units, with the only shared unit among classes being the engineer. The offence class is focused on tank-based, front-line combat, relying less on any kind of fortified emplacements or bases. The defence class is focused on infantry-based combat as well as utilization of rudimentary base defenses, and are also the only class to have access to superweapons. The support class is focused on air-combat and specialized vehicles to traverse the environment, and is also equipped with special support powers that are used to assist teammates. Command & Conquer 4 contains two non-playable factions from previous games in the Tiberium Universe: The Scrin (C&C3) and the Forgotten (Tiberian Sun), the latter of which returning as a minor part of the story as well as a neutral class on the map. Command & Conquer 4 includes a total of about 90 units, including many new units and updated versions of previous Command & Conquer units. The GDI utilizes walkers and powered armor infantry for its army whereas Nod primarily relies on cyborgs and treaded vehicles.

In Command and Conquer 4: Tiberian Twilight, each faction features its own campaign with the story told and played out from their perspective, each resulting in an ultimate conclusion to the Kane saga. In addition to the two brief single player campaigns, Command & Conquer 4: Tiberian Twilight features a cooperative campaign mode, which will allow multi-class play and integrated player progression. The difficulty in co-op campaign mode varies depending on the player's level, and objectives will be shared. Campaigns for both factions take place simultaneously.